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| Open AccessUSP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus: an epigenetic mechanism involved in cocaine use disorder
This study uncovers the role of epigenetic H2A monoubiquitination in the mouse brain’s response to chronic cocaine use. It also identifies genetic variations in humans linked to H2A monoubiquitination, modifying susceptibility to cocaine addiction and aggression, and paving the way for tailored treatments.
- Julian Cheron
- , Leonardo Beccari
- & Alban de Kerchove d’Exaerde
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| Open AccessInvestigation of monoclonal antibody CSX-1004 for fentanyl overdose
Fentanyl continues to drive the opioid crisis by contributing to >70,000 deaths per year in the US. Here, the authors investigate a candidate medication for fentanyl overdose prevention (monoclonal antibody CSX-1004) demonstrating its mitigation of fentanyl’s effects in preclinical animal models.
- Paul T. Bremer
- , Emily L. Burke
- & Rajeev I. Desai
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| Open AccessSingle nucleus transcriptomics of ventral midbrain identifies glial activation associated with chronic opioid use disorder
The cellular signatures of the opioid exposed human midbrain remain unexplored. Here, authors show by single nuclei transcriptomics activation of the glial immune response and dysregulation of synaptic signaling in opioid exposed individuals
- Julong Wei
- , Tova Y. Lambert
- & Schahram Akbarian
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Article
| Open AccessAssociation between vmPFC gray matter volume and smoking initiation in adolescents
The relationship between brain development and smoking behaviour is not well understood. Here, the authors show an association between volume of the left ventromedial prefrontal cortex and smoking initiation in adolescents.
- Shitong Xiang
- , Tianye Jia
- & Jianfeng Feng
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| Open AccessProfiling neuronal methylome and hydroxymethylome of opioid use disorder in the human orbitofrontal cortex
Opioid use disorder (OUD) is influenced by genetic and environmental factors. Here, authors use a multi-omics approach to reveal DNA hydroxymethylation as an important gene regulatory mechanism for OUD in the human brain.
- Gregory Rompala
- , Sheila T. Nagamatsu
- & Janitza L. Montalvo-Ortiz
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| Open AccessCocaine induces locomotor sensitization through a dopamine-dependent VTA-mPFC-FrA cortico-cortical pathway in male mice
The prefrontal cortex is involved in cocaine abuse disorders. Here, the authors show that cocaine suppresses frontal association cortex (FrA) in awake mice and induces locomotor sensitization through a dopamine dependent VTA-vmPFC-FrA pathway.
- Lun Wang
- , Min Gao
- & Zhuan Zhou
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| Open AccessCompulsive alcohol drinking in rodents is associated with altered representations of behavioral control and seeking in dorsal medial prefrontal cortex
Compulsive alcohol drinking is a core feature of alcohol use disorder. Here the authors find that in rodents, neural signals in a key decision-making brain region (dmPFC) shift from behavioral control to alcohol seeking during compulsive alcohol drinking behaviour.
- Nicholas M. Timme
- , Baofeng Ma
- & Christopher C. Lapish
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| Open AccessThe paraventricular thalamus provides a polysynaptic brake on limbic CRF neurons to sex-dependently blunt binge alcohol drinking and avoidance behavior in mice
Bed nucleus of the stria terminalis (BNST) neurons that synthesize and release the stress neuropeptide corticotropin-releasing factor drive binge alcohol drinking and anxiety. The authors describe a complex feedforward inhibitory PVTVGLUT2-BNSTCRF circuit in mice that plays sex-dependent roles in alcohol drinking and avoidance behavior.
- Olivia B. Levine
- , Mary Jane Skelly
- & Kristen E. Pleil
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| Open AccessA common limiter circuit for opioid choice and relapse identified in a rodent addiction model
The neural circuits underlying rewarding effects of drugs of abuse and natural rewards are not fully understood. Here the authors investigate the role of the infralimbic cortex to nucleus accumbens shell pathway during heroin or food choice in rats.
- Jasper A. Heinsbroek
- , Giuseppe Giannotti
- & Jamie Peters
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| Open AccessBrain-specific inhibition of mTORC1 eliminates side effects resulting from mTORC1 blockade in the periphery and reduces alcohol intake in mice
Chronic use of mTORC1 inhibitors produces undesirable side effects in humans which limit their value for CNS disorders treatment. The authors present a binary drug strategy to protects mTORC1 activity in the periphery and show its potential utility in preclinical models of alcohol use disorder.
- Yann Ehinger
- , Ziyang Zhang
- & Dorit Ron
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| Open AccessEndocannabinoid signaling regulates the reinforcing and psychostimulant effects of ketamine in mice
Ketamine is used for sedation and treatment of depression, but is also a drug of abuse. Here the authors show that ketamine modulates the endocannabinoid system in mice, and that this may contribute to its psychoactive effects.
- Wei Xu
- , Hongchun Li
- & Xiaobo Cen
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| Open AccessChromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder
Epigenetic mechanisms have emerged as contributors to the molecular impairments caused by exposure to environmental factors such as abused substances. Here the authors perform epigenetic profiling of the striatum and identify the tyrosine kinase FYN is an important driver of neurodegenerative-like pathology and drug-taking behaviour.
- Gabor Egervari
- , Diana Akpoyibo
- & Yasmin L. Hurd
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| Open AccessGestational alcohol exposure disrupts cognitive function and striatal circuits in adult offspring
Alcohol is the leading cause of preventable birth defects in the US, collectively referred to as Fetal Alcohol Spectrum Disorder. Here, the authors show that fetal alcohol exposure induces lasting neurophysiological changes in dorsal striatum that contribute to less efficient decision making.
- Verginia C. Cuzon Carlson
- , Christina M. Gremel
- & David M. Lovinger
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| Open AccessA specific prelimbic-nucleus accumbens pathway controls resilience versus vulnerability to food addiction
Food addiction is linked to obesity and eating disorders. In a mouse model of food addiction, the authors show that a medial prefrontal cortex-nucleus accumbens pathway is involved in vulnerability and resilience against the development of food addiction-like behavior.
- Laura Domingo-Rodriguez
- , Inigo Ruiz de Azua
- & Rafael Maldonado
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| Open AccessNr4a1 suppresses cocaine-induced behavior via epigenetic regulation of homeostatic target genes
The regulation of gene expression underlies many forms of learning and behaviour in the mammalian brain. Carpenter et al. define a molecular mechanism whereby Nr4a1 activation leads to persistent changes in gene expression, chromatin and behaviour, in the context of cocaine abstinence.
- Marco D. Carpenter
- , Qiwen Hu
- & Elizabeth A. Heller
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Article
| Open AccessKetamine can reduce harmful drinking by pharmacologically rewriting drinking memories
Memories linking environmental cues to alcohol reward are involved in the development and maintenance of heavy drinking. Here, the authors show that a single dose of ketamine, given after retrieval of alcohol-reward memories, disrupts the reconsolidation of these memories and reduces drinking in humans.
- Ravi K. Das
- , Grace Gale
- & Sunjeev K. Kamboj
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| Open AccessAnti-relapse neurons in the infralimbic cortex of rats drive relapse-suppression by drug omission cues
Drug addiction is a chronic disorder and many sufferers experience relapses even after a period of successful abstinence. Here, the authors reveal a subset of neurons in the rat infralimbic cortex that suppresses relapse into cocaine or alcohol use by responding to drug-omission cues.
- Amanda Laque
- , Genna L. De Ness
- & Nobuyoshi Suto
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| Open AccessGenome-wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations
The genetic underpinnings of alcohol use disorder and consumption are incompletely understood. Here, the authors perform GWAS for Alcohol Use Disorder (AUD) Identification Test-Consumption scores and AUD diagnosis from electronic health records of 274,424 individuals and identify a total of 18 associated loci.
- Henry R. Kranzler
- , Hang Zhou
- & Joel Gelernter
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| Open AccessInactivation of a CRF-dependent amygdalofugal pathway reverses addiction-like behaviors in alcohol-dependent rats
Withdrawal from alcohol activates neurons in the central amygdala (CeA) and increases craving for alcohol. The authors show that these neurons predominantly express CRF and project to the BNST. Inactivation of this pathway reduces the dependence-related escalation of alcohol drinking.
- Giordano de Guglielmo
- , Marsida Kallupi
- & Olivier George
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| Open AccessPhosphorylation-deficient G-protein-biased μ-opioid receptors improve analgesia and diminish tolerance but worsen opioid side effects
Tolerance and other side effects are important limitations to the use of opioids as analgesics. In this study, the authors generated mice lacking phosphorylation sites on the µ-opioid receptor to assess their contribution to the analgesic, tolerance and side effect profile of opioid analgesics.
- A. Kliewer
- , F. Schmiedel
- & S. Schulz
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| Open AccessGranulocyte-colony stimulating factor controls neural and behavioral plasticity in response to cocaine
Cocaine addiction is accompanied by dysfunction in neural circuits related to reward, but it is unclear how these adaptations occur. Here, authors identify granulocyte-colony stimulating factor as a potent mediator of cocaine-induced adaptations, and show that it can alter the motivation for cocaine.
- Erin S. Calipari
- , Arthur Godino
- & Drew D. Kiraly
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| Open AccessThe sigma-1 receptor modulates methamphetamine dysregulation of dopamine neurotransmission
The dopamine transporter (DAT), a regulator of dopamine homeostasis in the brain, and sigma-1 receptor (σ1R), an endoplasmic reticulum membrane protein, are both implicated in drug addiction. In this work, the authors investigate how σ1R modulates DAT response to methamphetamine.
- Danielle O. Sambo
- , Min Lin
- & Habibeh Khoshbouei
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Article
| Open AccessMidbrain circuit regulation of individual alcohol drinking behaviors in mice
Mice exposed to a two-bottle alcohol choice paradigm can be divided into high and low drinking groups. Here, the authors show that stimulating VTA neurons to induce higher phasic activity patterns that are observed in low alcohol drinking mice, suppresses alcohol drinking in mice that are high alcohol drinking.
- Barbara Juarez
- , Carole Morel
- & Ming-Hu Han
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Article
| Open AccessDrug-seeking motivation level in male rats determines offspring susceptibility or resistance to cocaine-seeking behaviour
Drug addiction is partially heritable but the non-genetic inheritance mechanisms are not well understood. The authors show that motivation of male rats in response to cocaine self-administration elicit susceptibility and/or decreased resistance to developing addiction like behaviour in offspring.
- Qiumin Le
- , Biao Yan
- & Lan Ma
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| Open AccessDopaminergic dynamics underlying sex-specific cocaine reward
Sex differences in reward processing are at present poorly understood. Calipari and Juarezet al. report oestrous cycle-dependent fluctuations in firing of VTA dopamine neurons that drive alterations in DAT function expressed in terminals in the NAc. These differences underlie enhanced cocaine reward processing during oestrus.
- Erin S. Calipari
- , Barbara Juarez
- & Eric J Nestler
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| Open AccessFMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties
Alcohol is thought to lead to neuroadaptive changes, although the underlying molecular mechanisms are unclear. Here, the authors find ethanol treatment alters GABAB-receptor expression via fragile-X mental retardation protein in mice, leading to antidepressant-like behaviours.
- Sarah A. Wolfe
- , Emily R. Workman
- & Kimberly F. Raab-Graham
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| Open AccessRegulation of claudin/zonula occludens-1 complexes by hetero-claudin interactions
Alcohol abuse is a risk factor for acute respiratory distress syndrome, flooding of the lungs due to compromised barrier function. Here the authors report that alcohol upregulates claudin-5 that is then recruited to tight junctions in alveolar epithelial cells, causing the displacement of claudin-18 from ZO-1 and diminished barrier function.
- Barbara Schlingmann
- , Christian E. Overgaard
- & Michael Koval
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| Open AccessOrexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons
Stress is a major cause of relapse to cocaine seeking behaviour. Tung et al. show that orexin mediates stress-induced reinstatement of cocaine seeking behaviour in mice by endocannabinoid-dependent disinhibition in the ventral tegmental area.
- Li-Wei Tung
- , Guan-Ling Lu
- & Lih-Chu Chiou
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| Open AccessBasolateral and central amygdala differentially recruit and maintain dorsolateral striatum-dependent cocaine-seeking habits
Drug seeking behaviour has habitual neural substrates. Here, Murray et al. show that the basolateral amygdala and central nucleus of the amygdala are necessary to recruit and maintain, respectively, the intrastriatal functional transition that underlies cocaine seeking habits.
- Jennifer E. Murray
- , Aude Belin-Rauscent
- & David Belin
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| Open AccessA novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking
Cue-based therapies for treating drug addiction have proven to be only partially effective. Here the authors demonstrate a new memory retrieval based treatment protocol for drug addiction that results in long-lasting inhibition of drug seeking behavior in rodents.
- Yi-xiao Luo
- , Yan-xue Xue
- & Lin Lu
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Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal
Abstinent smokers experience affective withdrawal symptoms that contribute to relapse, yet the circuitry and mechanisms underlying these symptoms are unknown. Here the authors identify a critical role for a ventral tegmental area-habenula-interpeduncular circuit in nicotine withdrawal-induced anxiety.
- Rubing Zhao-Shea
- , Steven R. DeGroot
- & Andrew R. Tapper
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Modulation of dopamine release in the striatum by physiologically relevant levels of nicotine
Nicotine exposure from cigarette smoke modulates dopamine release in the brain, which is implicated in nicotine addiction, but how it does this is unclear. Here, in mouse brain slices, the authors show that nicotine inhibits cholinergic- but not dopaminergic-dependent dopamine release.
- Li Wang
- , Shujiang Shang
- & Zhuan Zhou
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Mutations in the Gabrb1 gene promote alcohol consumption through increased tonic inhibition
Mutations in the GABA A receptor have been implicated in alcohol dependence in humans. In this study, the authors show that mice with mutations in the beta 1 subunit of the GABA A receptor exhibit spontaneous GABA A channel opening and preferentially consume alcohol, working harder to access it.
- Quentin M. Anstee
- , Susanne Knapp
- & Howard C. Thomas
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Methylphenidate amplifies the potency and reinforcing effects of amphetamines by increasing dopamine transporter expression
Methylphenidate, the active compound in Ritalin, is used to treat attention and hyperactivity disorders, but it is also taken for recreational use. Calipari et al.show that high-dose methylphenidate leads to enhanced dopaminergic responses to amphetamines, and enhanced amphetamine-seeking behaviour in rats.
- Erin S. Calipari
- , Mark J. Ferris
- & Sara R. Jones
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| Open AccessHypothalamic proteoglycan syndecan-3 is a novel cocaine addiction resilience factor
The lateral hypothalamus is implicated in drug reward and addiction. Chen and colleagues find that in the lateral hypothalamus of mice, the proteoglycan syndecan-3 negatively regulates cocaine-seeking behaviour by modulating the effects of glial cell line-derived neurotrophic factor.
- Jihuan Chen
- , Vez Repunte-Canonigo
- & Pietro Paolo Sanna
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Role of dopamine D2 receptors in plasticity of stress-induced addictive behaviours
Synaptic plasticity in the nucleus accumbens is implicated in stress and addiction. Sim et al. study mice deficient in dopamine D2 receptors, and find an increase in anxiety behaviour and reduced addictive behaviour in response to stress, both of which are associated with changes in nucleus accumbens activity.
- Hye-ri Sim
- , Tae-Yong Choi
- & Ja-Hyun Baik